Crystalline forms of n-[2-[[(2,3-difluorophenyl)methyl]thio]-6--4-pyrimidinyl]-1-azetidinesulfonamide

ABSTRACT

There is provided crystalline forms of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-{[(1R,2S)-2,3-dihydroxy-1-methylpropyl]oxy}-4-pyrimidinyl]-1-azetidinesulfon-amide anhydrate. Such compounds/forms may be useful in the treatment of a disease/condition in which modulation of chemokine receptor activity is beneficial.

This application claims the benefit under 35 U.S.C. §119(e) ofApplication No. 61/363,726 (US) filed on 13 Jul. 2010.

This invention relates to new solid state forms of a drug, topharmaceutical compositions containing them, and to processes forobtaining them.

In the formulation of drug compositions, it is desirable for the drugsubstance to be in a form in which it can be conveniently handled andprocessed. This is of importance, not only from the point of view ofobtaining a commercially viable manufacturing process, but also from thepoint of view of subsequent manufacture of pharmaceutical formulationscomprising the active compound.

Chemical stability, solid state stability, and “shelf life” of theactive ingredients are also very important factors. The drug substance,and compositions containing it, should be is capable of beingeffectively stored, without exhibiting a significant change in theactive component's physico-chemical characteristics (e.g. its chemicalcomposition, density, hygroscopicity and solubility).

Moreover, it is also desirable to be able to provide drug in a formwhich is as chemically pure as possible.

Amorphous, or semi-amorphous materials may present significant problemsin this regard. For example, such materials are typically difficult tohandle and to formulate, provide for unreliable solubility, and areoften found to be unstable and chemically impure.

The skilled person will appreciate that, if a drug can be readilyobtained in a stable crystalline form, the above problems may be solved.

Furthermore, crystalline drug compounds have been shown to provide morereliable and reproducible plasma concentration profiles followingadministration to a patient.

Thus, in the manufacture of commercially viable, and pharmaceuticallyacceptable, drug compositions, it is desirable, wherever possible, toprovide drug in a substantially crystalline, and stable, form.

It is to be noted, however, that this goal is not always achievable.Indeed, typically, it is not possible to predict, from molecularstructure alone, what the crystallisation behaviour of a compound willbe. This can usually only be determined empirically.

International patent application WO 2006/024823 discloses a number ofpyrimidine sulphonamide derivatives as chemokine receptor modulators,including the specific compoundN-[2-[[(2,3-difluorophenyl)methyl]thio]-6-{[(1R,2S)-2,3-dihydroxy-1-methylpropyl]oxy}-4-pyrimidinyl]-1-azetidinesulfonamide(Example 47):

also referred to herein as Compound I.

WO 2006/024823 discloses a process for preparing Compound I, but doesnot disclose any specific information regarding crystalline forms ofthat compound.

We have now found that it is possible to produce stable, crystallineforms of Compound I, or a pharmaceutically acceptable salt thereof,which crystalline forms may be referred to herein at the “compounds ofthe invention”.

According to an aspect of the invention, there is provided asubstantially crystalline form of Compound I, or a pharmaceuticallyacceptable salt thereof (for the avoidance of doubt, these are“compounds of the invention”).

In another aspect of the invention, there is provided a crystalline formof Compound I, or a pharmaceutically acceptable salt thereof.

According to a further aspect of the invention, there is provided asubstantially crystalline anhydrate form of Compound I (for theavoidance of doubt, these are “compounds of the invention”). In oneaspect, Compound I is not in the form of a salt. It is further preferredthat it is not in the form of a solvate, i.e. it is an “ansolvate”.Hence, the term “anhydrate” encompasses “ansolvate”.

We have found that Compound I may be obtained in forms that aresubstantially crystalline in nature. Although it is possible to produceCompound I in forms that are greater than about 90%, such as greaterthat about 95%, crystalline (e.g. greater than about 98% crystallineand, particularly, 100%, or nearly 100%, crystalline), by “substantiallycrystalline” we include greater than about 60%, in another aspectgreater than about 75%, and in yet another aspect greater than about 80%(such as about 90%) crystalline. The degree (%) of crystallinity may bedetermined by the skilled person using X-ray powder diffraction (XRPD).Other techniques, such as solid state NMR, FT-IR, Raman spectroscopy,differential scanning calorimetry (DSC) microcalorimetry, andcalculations of the true density, may also be used.

Suitable a crystalline modification of a compound according to theinvention is to substantially free from other crystalline modificationsof the compound. Suitably, a described crystalline modification of acompound of formula I includes less than, for example 20%, 15%, 10%, 5%,3% or particularly, less then 1% by weight of other crystalline forms ofthat compound.

It is stated hereinbefore that Compound I may be produced in acrystalline form that is an anhydrate. By this we mean that thecrystalline form contains less than 10% of (a) hydrate form(s) (e.g. amonohydrate) of Compound I.

Two preferred anhydrate crystalline forms of Compound I may becharacterised by an X-ray powder diffraction pattern, using X-rays ofwavelength 1.5418 Å, comprising the following characteristic crystallinepeaks with approximate 2-Theta values (in degrees) as well as anindication of the relative intensity of those peaks in brackets, where apercentage relative intensity of approximately 25-100% is termed “vs”,approximately 10-25% is termed “s”, approximately 3-10% is termed “m”and approximately 1-3% is termed “w”:

Form A: characteristic crystalline peaks with at least one 2-Thetavalues (in degrees) of around (i.e. at about or at approximately) 14.8,17.8 and/or 24.1. In one aspect, characteristic crystalline peaks withat least one 2-Theta values (in degrees) of 14.8, 17.8 and/or 24.1. Inanother aspect, all of these peaks are present. In yet another aspect,also comprising at least one further crystalline peaks with a 2-Thetavalue (in degrees) of around (i.e. at about or at approximately) 16.3,15.5, 11.4, 9.9, 13.1 and/or 4.4. In yet another aspect, all of theaforementioned peaks are present. In yet another aspect, also comprisingat least one further crystalline peaks with a 2-Theta value (in degrees)of 16.3, 15.5, 11.4, 9.9, 13.1 and/or 4.4. In another aspect, all of theaforementioned peaks are present.

In another aspect, form A has characteristic crystalline peaks with atleast one 2-Theta values (in degrees) of around (i.e. at about or atapproximately) 14.8 (s), 17.8 (vs) and/or 24.1 (vs). In one aspect, allof these peaks are present. In another aspect, also comprising at leastone further crystalline peaks with a 2-Theta value (in degrees) ofaround (i.e. at about or at approximately) 16.3 (s), 15.5 (s), 11.4(vs), 9.9 (vs), 13.1 (vs) and/or 4.4 (vs). In another aspect, all ofthese peaks are present. In one aspect, the form comprises all thecharacteristic peaks (e.g. with the indicated relative intensity) asshown to by Example 1 hereinafter and hence the form may becharacterised by the X-ray powder diffractogram that is essentially thatshown in FIG. 1.

Form D: characteristic crystalline peaks with at least one 2-Thetavalues (in degrees) of around (i.e. at about or at approximately) 12.9,18.0 and/or 21.0. In one aspect, all of these peaks are present. Inanother aspect, also comprising at least one further crystalline peakwith a 2-Theta value (in degrees) of around (i.e. at about or atapproximately) 25.1, 25.3, 27.0 and/or 29.1. In yet another aspect, allof these peaks are present.

In another aspect, form D has characteristic crystalline peaks with atleast one 2-Theta values (in degrees) of around (i.e. at about or atapproximately) 12.9 (vs), 18.0 (vs) and/or 21.0 (s). In one aspect, allof these peaks are present. In another aspect, also comprising at leastone further crystalline peak with a 2-Theta value (in degrees) of around(i.e. at about or at approximately) 25.1 (s), 25.3 (s), 27.0 (s) and/or29.1 (s). In yet another aspect, all of these peaks listed for form Dare present. In another aspect, the form comprises all thecharacteristic peaks (e.g. with the indicated relative intensity) asshown by Example 2 hereinafter and hence the form may be characterisedby the X-ray powder diffractogram that is essentially that shown in FIG.2.

In another aspect form D is characterised by a powder X-ray diffractionpattern, measured using a wavelength of X-rays 1.5418 Å, comprising atleast 1 crystalline peak with a 2-Theta value (in degrees) of 21.0, 28.8and/or 29.1.

In another aspect form D is characterised by a powder X-ray diffractionpattern, measured using a wavelength of X-rays 1.5418 Å, comprising atleast 2 crystalline peaks with a 2-Theta value (in degrees) of 21.0,28.8 and/or 29.1.

In another aspect form D is characterised by a powder X-ray diffractionpattern, measured using a wavelength of X-rays 1.5418 Å, comprising atleast 3 crystalline peaks with a 2-Theta value (in degrees) of 21.0,28.8 and/or 29.1.

In another aspect form D is characterised by a powder X-ray diffractionpattern, measured using a wavelength of X-rays 1.5418 Å, comprising afurther crystalline peak with a 2-Theta value (in degrees) selected fromof 12.9 and 18.0.

In another aspect form D is characterised by a powder X-ray diffractionpattern, measured using a wavelength of X-rays 1.5418 Å, comprisingcrystalline peaks with a 2-Theta value (in degrees) of 12.9, 13.1, 18.0,21.0, 22.5, 25.1, 25.3, 28.8, 29.1 and 30.4.

In one aspect, compounds of the invention are substantiallycrystallographically pure. By “substantially crystallographically pure”we include a crystalline form of Compound I anhydrate, as far as can bejudged by X-ray Powder Diffraction (XRPD) measurements, that containsless than about 5%, in another aspect less than about 3% and in yetanother aspect less than about 1% of other crystalline forms of theCompound I (whether it is another anhydrate form or otherwise, and asjudged by the presence of XRPD peaks from such other crystalline forms).

DSC analysis shows Form D has an onset of melting at 152.7° C. The DSCthermogram is depicted in FIG. 3. In one aspect the invention relates toa crystalline form of the compound of formula I with a melting point ofabout 152.7° C. (onset).

We have found that, for certain anhydrates of Compound I, solvent drying(during the crystallisation process) is not necessary to ensureformation. However, to ensure that anhydrate is produced, the solventfrom which the crystallisation occurs may be dried, either before orduring the crystallisation process, in order to reduce the water contentbelow a critical level, which should preferably not be exceeded duringthe crystallisation. Solvent may be dried during the crystallisationprocess, for example by decreasing the water content of a mixture of thecompound to be crystallised and an appropriate organic solvent/aqueoussolvent system (e.g. by increasing the amount of organic solvent that ispresent and/or removal of water by formation of an azeotrope, withsuccessive distillations).

Hence, the anhydrate of Compound I may be produced by crystallisationfrom a solvent system which is substantially free of water.

By “substantially free of water”, we include that the water content inthe solvent system is below that which will result in the formation of,at most, 10% monohydrate, for any particular solvent system and set ofcrystallisation conditions.

Crystalline Form D of Compound I anhydrate may be prepared by suspensionof Compound I (e.g. in amorphous form or hi a different crystallineform, such as the Form A) in a solvent system. There is thereforeprovided a crystalline form obtainable by such a (crystallisation)conversion process. The skilled person will understand that a suspensionto process is essentially a “slurrying” process or a process thatinvolves at least partial (but not complete) dissolution in a solventsystem.

In an aspect of the invention therefore, there is provided theconversion of one crystalline form (e.g. one anhydrate form) of CompoundIto another. In particular the Form A (also referred to herein as theA-form) may be converted to the Form D (also referred to herein as theD-form). Again, there is therefore provided a crystalline formobtainable by such a (crystallisation) conversion process.

In order to obtain the D-form, the A-form may be suspended or slurried(or at least partially dissolved) in a solvent system that does notpromote the formation of a solvate form of Compound I.

The terms “suspended” and “slurried” (or “partially dissolved”) are wellunderstood by the skilled person. For instance to form a suspension orslurry, an excess of the solid substance, relative to the solubility inthe solvent, is added such that there is (undissolved) solid in thesolvent system throughout the “suspension” or “slurrying” procedure.Hence why it is also referred to herein as “partial dissolution”.

Preferred solvent systems employed to obtain the D-form by suspension orslurrying (i.e. to achieve the conversion of e.g. the amorphous CompoundI or the A-form, to the D-form) include any suitable solvent (alsoreferred to herein as “the suspension solvent”), or mixture of solvents,that do not result in the formation of a solvate of Compound I.Preferred solvent systems may include those in which the Compound I isonly partially (or is at least partially) soluble. In one aspect, thesolvent system comprises (or, in another aspect, consists essentiallyof) organic solvents that are polar, e.g. alcohols (such as lower alkylalcohols, e.g. a C₁₋₆ alcohol). In another aspect, the solvent systemcomprises (or, in another aspect, consists essentially of) ethanol or,especially, methanol. Hence, the aforementioned polar organic solventsare the particularly preferred suspension solvents employed in thesolvent system (and in another aspect, the solvent system consistsprimarily or essentially of such suspension solvents). In one aspect,the suspension solvent (e.g. alcohol, such as methanol) constitutes atleast 90% w/w (e.g. at least 95%, such as about 100%) of the totalsolvent system that is employed to obtain the D-form. That is, thesuspension solvent may contain up to 10% w/w (e.g. up to 5%, or about0%) of other (undesired or less desired) solvents.

The phase conversion in the solvent system (including the suspensionsolvent, as hereinbefore described) to obtain the D-form may take up toa period of weeks (e.g. six weeks; see the Example hereinafter), but thelength of time may be reduced depending on the temperature of theprocess (or it may take longer if performed at lower temperatures), etc.However, the skilled person can easily determine the length of timetaken for conversion to the D-form. Furthermore, the D-form may beobtained by seeding, for example as described hereinafter.

The A-form of Compound I may be crystallised from the amorphous form ofCompound I in a mixture containing a certain solvent (e.g.acetonitrile), an inorganic acid (e.g. phosphoric acid) and water, whichmixture may be heated and then cooled to promote crystallisation, asdescribed hereinafter (see e.g. Example 2).

The A-form of Compound I may be crystallised fromN-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy]-4-pyrimidinyl]-1-azetidinesulfonamidein a mixture containing a certain solvent (e.g. acetonitrile), aninorganic acid (e.g. phosphoric acid) and water, which mixture may beheated and then cooled to promote crystallisation, as describedhereinafter (see e.g. Example 2).

Crystallisations described herein may also be promoted by the additionof seed crystals (once available).

For instance, the D-form may also be prepared by seeding, using thefollowing procedure: dissolving Compound I (e.g. one ‘weight’ %) in asolvent (such as an alcohol, e.g. isopropanol; e.g. 30 relativevolumes); stirring at elevated temperature (e.g. 70° C.) for instancefor a period of time (which may be several hours) to achieve the fulldissolution; continuing stirring at elevated temperature (e.g. 55° C.;i.e. at a temperature lower than that required to achieve dissolution)for a period of time e.g. several hours (e.g. overnight); seeding withForm D of Compound I (e.g. 0.1 weight %); cooling to a lower temperature(e.g. 20° C.); and filtering to yield the D-form.

Alternatively, the D-form may also be prepared by seeding, using thefollowing procedure: dissolving Compound I (e.g. one relative ‘weight’%) in a solvent (such as an alcohol, e.g. ethanol; e.g. 15 relativevolumes); stirring at elevated temperature (e.g. 65° C.) for instancefor a period of time (which may be several hours) to achieve the fulldissolution; continuing stirring at elevated temperature (e.g. 55° C.;i.e. at a temperature lower than that required to achieve dissolution)for a period of time e.g. several hours (e.g. overnight); seeding withForm D of Compound I (e.g. 0.1 weight %); cooling to a lower temperature(e.g. 20° C.); and filtering to yield the D-form.

In order to ensure that crystalline forms as described herein areprepared in the absence of other crystalline forms, crystallisations maybe carried out by seeding with nuclei and/or seed crystals of thedesired crystalline form in the absence of nuclei and/or is seedcrystals of other crystalline forms.

The skilled person will appreciate that the concentration in solution ofthe compound that is to be crystallised, and the solvent system that isused, may influence crystallisation temperatures and crystallisationtimes.

Different crystalline forms may have different solubility in differentorganic solvents at any given temperature. In this respect,above-mentioned, or other, solvents may be employed as “antisolvents”(i.e. a solvent in which compounds of the invention are poorly soluble,but which is miscible with another solvent, in which compounds of theinvention are more soluble), and may thus aid the crystallisationprocess.

As may be appreciated by the skilled person, the crystalline form thatis obtained depends upon both the kinetics and the thermodynamics of thecrystallisation process. Under certain thermodynamic conditions (solventsystem, temperature, pressure and concentration of the compound of theinvention), one crystalline form may be more stable than another (orindeed any other). However, other crystalline forms that may have, incomparison, a relatively low thermodynamic stability, may bekinetically-favoured. Thus, in addition, kinetic factors, such as time,impurity profile, agitation, the presence of seeds, etc. may alsoinfluence which forms appear. Thus, the procedures discussed herein maybe adapted by the skilled person as appropriate in order to obtain theparticular crystalline form of Compound I (e.g. the A-form or D-form).

Further, drying temperature and drying time may affect the solid stateproperties and/or the solid state form of compounds of the invention.For example, dehydration may occur at low humidity and/or elevatedtemperatures and/or reduced pressure. Hence, the crystalline anhydratesof compounds of the invention may also be formed by dehydration of ahydrate.

As stated hereinbefore, preferred compounds of the invention may also becharacterised by a powder X-ray diffraction pattern that is essentiallyaccording to that to shown in FIG. 1 or FIG. 2 attached hereto and/or astabulated in Table 1 or Table 2 hereinafter (see Examples 1 and 2). Theskilled person will appreciate that a form of a crystalline anhydrateform of Compound I shows “essentially” the same powder X-ray diffractionpattern as another when it was clear to that skilled person from therespective patterns (i.e. the relative spacing of the peaks, allowingfor experimental error, such as is preferred orientation of the sampleand respective instrument settings (e.g. apparatus type, standardizationand/or calibration)) that the same crystalline form has been formed.Thus, there may be some experimental error for ° 2 Theta values as maybe specified herein (e.g. a variation of up ±0.5° 2-theta).

We have found that the compounds of the invention have a surprisinglyimproved physical and/or chemical stability when compared with otherforms of Compound I that may have previously been prepared.

The term “stable” as defined herein includes chemical stability andsolid state stability.

By “chemical stability”, we include that the compound can be stored inan isolated solid form, or in the form of a solid formulation in whichit may be provided in admixture with pharmaceutically acceptablecarriers, diluents or adjuvants, under normal storage conditions, withan insignificant degree of chemical degradation or decomposition.

By “solid state stability”, we include that the compound can be storedin an isolated solid form, or in the form of a solid formulation inwhich it may be provided in admixture with pharmaceutically acceptablecarriers, diluents or adjuvants, under normal storage conditions, withan insignificant degree of solid state transformation (e.g.crystallisation, recrystallisation, loss of crystallinity, solid statephase transition, hydration, dehydration, solvatisation ordesolvatisation).

Examples of “normal storage conditions” include temperatures of betweenminus 80 and plus 50° C. (in one aspect between 0 and 40° C. and inanother aspect at ambient temperature, such as between 15 and 30° C.),pressures of between 0.1 and 2 bars (in one aspect at atmosphericpressure), and/or exposure to 460 lux of UV/visible light, for prolongedperiods (i.e. greater than or equal to six months). Under suchconditions, compounds of the invention may be found to be less thanabout 15%, in one aspect less than about 10%, and in another aspect lessthan about 5%, chemically degraded/decomposed, or solid-statetransformed, as appropriate. The skilled person will appreciate that theabove-mentioned upper and lower limits for temperature and pressurerepresent extremes of normal storage conditions, and that certaincombinations of these extremes will not be experienced during normalstorage (e.g. a temperature of 50° C. and a pressure of 0.1 bar).

The term “normal storage conditions” may also include relativehumidities of between 5 and 95% (in one aspect 10 to 60%). However, inthe case of certain crystalline forms according to the invention,changes in conformation or crystal structure by hydration and/ordehydration may occur as a result of prolonged exposure to certainextremes of relative humidities, at normal temperatures/pressures.

The preparation and characterisation of compounds of the invention aredescribed hereinafter. Different crystalline forms of the compounds ofthe invention may be readily characterised using X-ray powderdiffraction (XRPD) methods, for example as described hereinafter.

Compounds of the invention may be isolated using techniques which arewell known to those skilled in the art, for example decanting, filteringand/or centrifuging.

We have found that, by employing the crystallisation or conversionprocesses described herein, it is possible to produce compounds of theinvention with a high chemical purity.

When compounds of the invention are prepared as described herein, theresultant compound is in a form which has improved chemical and solidstate stability, as mentioned hereinbefore, as well as improvedsolubility and hygroscopicity profiles when compared to other previouslyknown forms.

Although in one aspect, compounds of the invention (i.e. the crystallineforms) are not in the form of salts, salts that may be mentioned includeacid addition salts and base addition salts.

Pharmaceutical Preparations and Medical Use

The compounds of the invention are useful because they possesspharmacological activity. They are therefore indicated aspharmaceuticals.

In particular, the compounds of the invention find utility in thetreatment of diseases/conditions in which modulation of chemokinereceptor activity, especially CXCR2, is beneficial.

The term “modulation” may refer to any measurable reduction and/orprevention of the relevant activity (chemokine receptor activity). Themodulation of chemokine receptor activity may be measured by comparingthe chemokine receptor activity in a sample containing a compound of theinvention and in a sample in the absence of a compound of the invention(as would be apparent to those skilled in the art). The measurablechange may be objective (e.g. measurable by some test or marker, forexample in an in vitro or in vivo assay or test, such as one describedhereinafter, or otherwise another suitable assay or test known to thoseskilled in the art) or subjective (e.g. the subject gives an indicationof or feels an effect).

The compound of formula (I) or pharmaceutically acceptable salts may beused in the treatment (therapeutic or prophylactic) ofconditions/diseases in human and non-human animals which are exacerbatedor caused by excessive or unregulated production of chemokines. Examplesof such conditions/diseases include (each taken independently):

(1) the respiratory tract—obstructive airways diseases including chronicobstructive pulmonary disease (COPD); asthma, such as bronchial,allergic, intrinsic, extrinsic and dust asthma, particularly chronic orinveterate asthma (e.g. late asthma and airways hyper-responsiveness);bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitisincluding rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta,rhinitis sicca and rhinitis medicamentosa; bronchiectasis; membranousrhinitis including croupous, fibrinous and pseudomembranous rhinitis andscrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hayfever) and vasomotor rhinitis; sarcoidosis, farmer's lung and relateddiseases, fibroid lung and idiopathic interstitial pneumonia;

(2) bone and joints—rheumatoid arthritis, seronegativespondyloarthropathies (including ankylosing spondylitis, psoriaticarthritis and Reiter's disease), Behchet's disease, Sjogren's syndromeand systemic sclerosis;

(3) skin—psoriasis, atopical dermatitis, contact dermatitis and othereczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus,bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas,vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopeciagreata and vernal conjunctivitis;

(4) gastrointestinal tract—Coeliac disease, proctitis, eosinopilicgastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis,indeterminate colitis, microscopic colitis, inflammatory bowel disease,irritable bowel syndrome, non-inflammatory diarrhea, food-relatedallergies which have effects remote from the gut, e.g., migraine,rhinitis and eczema;

(5) central and peripheral nervous system—Neurodegenerative diseases anddementia disorders, e g Alzheimer's disease, amyotrophic lateralsclerosis and other motor neuron diseases, Creutzfeldt-Jacob's diseaseand other prion diseases, HIV encephalopathy (AIDS dementia complex),Huntington's disease, frontotemporal dementia, Lewy body dementia andvascular dementia; polyneuropathies, e.g. Guillain-Barré syndrome,chronic inflammatory demyelinating polyradiculoneuropathy, multifocalmotor neuropathy, plexopathies; CNS demyelination, e.g. multiplesclerosis, acute disseminated/haemorrhagic encephalomyelitis, andsubacute sclerosing panencephalitis; neuromuscular disorders, e.g.myasthenia gravis and Lambert-Eaton syndrome; spinal diorders, e.g.tropical spastic paraparesis, and stiff-man syndrome: paraneoplasticsyndromes, e.g. cerebellar degeneration and encephalomyelitis; CNStrauma; migraine; and stroke.

(6) other tissues and systemic disease—atherosclerosis, AcquiredImmunodeficiency Syndrome (AIDS), lupus erythematosus, systemic lupus,erythematosus, Hashimoto's thyroiditis, type I diabetes, nephroticsyndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatousleprosy, and idiopathic thrombocytopenia pupura; post-operativeadhesions, and sepsis.

(7) allograft rejection—acute and chronic following, for example,transplantation of kidney, heart, liver, lung, bone marrow, skin andcornea; and chronic graft versus host disease;

(8) cancers—especially non-small cell lung cancer (NSCLC), malignantmelanoma, prostate cancer and squamous sarcoma, and tumour metastasis,non melanoma skin cancer and chemoprevention metastases;

(9) diseases—in which angiogenesis is associated with raised CXCR2chemokine levels (e.g. NSCLC, diabetic retinopathy);

(10) cystic fibrosis;

(11) burn wounds & chronic skin ulcers;

(12) reproductive diseases—for example disorders of ovulation,menstruation and implantation, pre-term labour, endometriosis;

(13) re-perfusion injury—in the heart, brain, peripheral limbs and otherorgans, inhibition of atherosclerosis.

Thus, the present invention provides a compound of formula (1), or apharmaceutically-acceptable salt as hereinbefore defined for use intherapy.

The compounds of the invention may be used to treat diseases in whichthe chemokine receptor is the CXCR2 receptor.

Particular conditions which may be treated with the compounds of theinvention are cancer, diseases in which angiogenesis is associated withraised CXCR2 chemokine levels, and inflammatory diseases such as asthma,allergic rhinitis, COPD, bronchiectasis, rheumatoid arthritis,psoriasis, inflammatory bowel diseases, osteoarthritis or osteoporosis.

In another aspect particular conditions which may be treated with thecompounds of the invention are asthma, COPD and bronchiectasis.

As a further aspect of the present invention, the compound of formula(I) may have utility as antagonists of the CX3CR1 receptor. Suchcompounds are expected to be particularly useful in the treatment ofdisorders within the central and peripheral nervous system and otherconditions characterized by an activation of microglia and/orinfiltration of leukocytes (e.g. stroke/ischemia and head trauma). Inparticular, the compounds are indicated for use in the treatment ofneurodegenerative disorders or demyelinating disease in mammalsincluding man. More particularly, the compounds are indicated for use inthe treatment of multiple sclerosis. The compounds are also indicated tobe useful in the treatment of pain, rheumatoid arthritis,osteoarthritis, stroke, atherosclerosis and pulmonary arterialhypertension.

In a further aspect, the present invention provides a compound offormula (1), or a pharmaceutically acceptable salt, as hereinbeforedefined for use as a medicament.

In a still further aspect, the present invention provides the use of acompound of formula (1), or a pharmaceutically acceptable salt, ashereinbefore defined for use as a medicament for the treatment of humandiseases or conditions in which modulation of chemokine receptoractivity is beneficial.

In a still further aspect, the present invention provides the use of acompound of formula (1), or a pharmaceutically acceptable salt, ashereinbefore defined for use as a medicament for the treatment ofasthma, allergic rhinitis, cancer, COPD, rheumatoid arthritis,psoriasis, inflammatory bowel diseases, osteoarthritis or osteoporosis.

In a further aspect, the present invention provides the use of acompound of formula (1), or a pharmaceutically acceptable salt, ashereinbefore defined in the manufacture of a medicament for use intherapy.

In a still further aspect, the present invention provides the use of acompound of formula (1), or a pharmaceutically acceptable salt, ashereinbefore defined in the manufacture of a medicament for thetreatment of human diseases or conditions in which modulation ofchemokine receptor activity is beneficial.

In a still further aspect, the present invention provides the use of acompound of formula (1), or a pharmaceutically acceptable salt, ashereinbefore defined in the manufacture of a medicament for thetreatment of asthma, allergic rhinitis, cancer, COPD, rheumatoidarthritis, psoriasis, inflammatory bowel diseases, osteoarthritis orosteoporosis.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention still further provides a method of treating a chemokinemediated disease wherein the chemokine binds to a chemokine (especiallyCXCR2) receptor, which comprises administering to a patient atherapeutically effective amount of a compound of formula, or apharmaceutically acceptable salt, as hereinbefore defined.

The invention also provides a method of treating an inflammatorydisease, especially asthma, allergic rhinitis, COPD, rheumatoidarthritis, psoriasis, inflammatory bowel diseases, osteoarthritis orosteoporosis, in a patient suffering from, or at risk of, said disease,which comprises administering to the patient a therapeutically effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt, as hereinbefore defined.

More specifically, the compounds of the invention may be useful in thetreatment of asthma, allergic rhinitis, COPD, inflammatory boweldisease, irritable bowel syndrome, osteoarthritis, osteoporosis,rheumatoid arthritis, psoriasis or cancer.

Compounds of the invention are indicated both in the therapeutic and/orprophylactic treatment of the above-mentioned conditions.

The term “atherosclerosis” will be understood by those skilled in theart to include any disease characterised by cholesterol accumulation,foam cell formation, inflammation and cell proliferation in a bloodvessel, especially an artery wall.

According to a further aspect of the invention there is provided amethod of treatment of a disease/condition in which modulation ofchemokine receptor activity is beneficial (e.g. a specificdisease/condition mentioned herein), which method comprises theadministration of a compound of the invention to a patient in need ofsuch treatment.

“Patients” include mammalian (including human) patients. Hence, themethod of treatment discussed above may include the treatment of a humanor animal body.

The term “effective amount” refers to an amount of a compound, whichconfers a therapeutic effect on the treated patient. The effect may beobjective (e.g. measurable by some test or marker) or subjective (e.g.the subject gives an indication of or feels an effect).

Compounds of the invention may be administered orally, intravenously,subcutaneously, buccally, rectally, dermally, nasally, tracheally,bronchially, sublingually, by any other parenteral route or viainhalation, in a pharmaceutically acceptable dosage form. For instance,the pharmaceutical compositions may be administered topically (e.g. tothe lung and/or airways or to the skin) in the form of solutions,suspensions, heptafluoroalkane aerosols and dry powder formulations; orsystemically, e.g. by oral administration in the form of tablets,capsules, syrups, powders or granules, or by parenteral administrationin the form of solutions or suspensions, or by subcutaneousadministration or by rectal administration in the form of suppositoriesor transdermally. In one aspect, the compounds of the invention areadministered orally.

Compounds of the invention may be administered alone, but are in oneaspect of the invention are administered by way of known pharmaceuticalformulations, including tablets, capsules or elixirs for oraladministration, suppositories for rectal administration, sterilesolutions or suspensions for parenteral or intramuscular administration,and the like. The type of pharmaceutical formulation may be selectedwith due regard to the intended route of administration and standardpharmaceutical practice. Such pharmaceutically acceptable carriers maybe chemically inert to the active compounds and may have no detrimentalside effects or toxicity under the conditions of use.

Such formulations may be prepared in accordance with standard and/oraccepted pharmaceutical practice. Otherwise, the preparation of suitableformulations may be achieved non-inventively by the skilled person usingroutine techniques and/or in accordance with standard and/or acceptedpharmaceutical practice.

According to a further aspect of the invention there is thus provided apharmaceutical formulation including a compound of the invention, ashereinbefore defined, in admixture with a pharmaceutically acceptableadjuvant, diluent and/or carrier. Such formulations may be administeredas described hereinbefore. The compound of the is invention (i.e. thecrystalline form) that is the active ingredient of the pharmaceuticalformulation may be milled or ground into smaller particles.

Depending on e.g. potency and physical characteristics of the compoundof the invention (i.e. active ingredient), pharmaceutical formulationsthat may be mentioned include those in which the active ingredient (i.e.the compound of the invention) is present in at least 1% (or at least10%, at least 30% or at least 50%) by weight. That is, the ratio ofactive ingredient to the other components (i.e. the addition ofadjuvant, diluent and carrier) of the pharmaceutical composition is atleast 1:99 (or at least 10:90, at least 30:70 or at least 50:50) byweight.

The amount of compound of the invention in the formulation will dependon the severity of the condition, and on the patient, to be treated, aswell as the compound(s) which is/are employed, but may be determinednon-inventively by the skilled person.

The invention further provides a process for the preparation of apharmaceutical formulation, as hereinbefore defined, which processcomprises bringing into association a compound of the invention, ashereinbefore defined, with a pharmaceutically-acceptable adjuvant,diluent or carrier.

Compounds of the invention may also be combined with other therapeuticagents, for instance those that are also useful in the treatment of adisease/condition in which modulation of chemokine receptor activity isbeneficial (e.g. those diseases/conditions mentioned herein). Compoundsof the invention may also be combined with other therapies.

According to a further aspect of the invention, there is provided acombination product comprising:

-   (A) a compound of the invention, as hereinbefore defined; and-   (B) another therapeutic agent that is useful in the treatment of a    disease/condition in which modulation of chemokine receptor activity    is beneficial (e.g. a disease/condition described herein),    wherein each of components (A) and (B) is formulated in admixture    with a pharmaceutically-acceptable adjuvant, diluent or carrier.

Such combination products provide for the administration of a compoundof the invention in conjunction with the other therapeutic agent, andmay thus be presented either as separate formulations, wherein at leastone of those formulations comprises a compound of the invention, and atleast one comprises the other therapeutic agent, or may be presented(i.e. formulated) as a combined preparation (i.e. presented as a singleformulation including a compound of the invention and the othertherapeutic agent).

Thus, there is further provided:(1) a pharmaceutical formulation including a compound of the invention,as hereinbefore defined, another therapeutic agent that is useful in thetreatment of a disease/condition in which modulation of chemokinereceptor activity is beneficial, and a pharmaceutically-acceptableadjuvant, diluent or carrier; and(2) a kit of parts comprising components:(a) a pharmaceutical formulation including a compound of the invention,as hereinbefore defined, in admixture with a pharmaceutically-acceptableadjuvant, diluent or carrier; and(b) a pharmaceutical formulation including another therapeutic agentthat is useful in the treatment of a disease/condition in whichmodulation of chemokine receptor activity is beneficial in admixturewith a pharmaceutically-acceptable adjuvant, diluent or carrier, whichcomponents (a) and (b) are each provided in a form that is suitable foradministration in conjunction with the other.

The invention further provides a process for the preparation of acombination product as hereinbefore defined, which process comprisesbringing into association a compound of the invention, as hereinbeforedefined, with the other therapeutic agent that is useful in thetreatment of cancer and/or a proliferative disease, and at least onepharmaceutically-acceptable adjuvant, diluent or carrier.

By “bringing into association”, we mean that the two components arerendered suitable for administration in conjunction with each other.

Thus, in relation to the process for the preparation of a kit of partsas hereinbefore defined, by bringing the two components “intoassociation with” each other, we include that the two components of thekit of parts may be:

(i) provided as separate formulations (i.e. independently of oneanother), which are subsequently brought together for use in conjunctionwith each other in combination therapy; or(ii) packaged and presented together as separate components of a“combination pack” for use in conjunction with each other in combinationtherapy.

Depending on the disorder, and the patient to be treated, as well as theroute of administration, compounds of the invention may be administeredat varying therapeutically effective doses to a patient in need thereof.However, the dose administered to a mammal, particularly a human, in thecontext of the present invention should be sufficient to effect atherapeutic response in the mammal over a reasonable timeframe. Oneskilled in the art will recognize that the selection of the exact doseand composition and the most appropriate delivery regimen will also beinfluenced by inter alia the pharmacological properties of theformulation, the nature and severity of the condition being treated, andthe physical condition and mental acuity of the recipient, as well asthe potency of the specific compound, the age, condition, body weight,sex and response of the patient to be treated, and the stage/severity ofthe disease.

Administration may be continuous or intermittent (e.g. by bolusinjection). The dosage may also be determined by the timing andfrequency of administration. In the case of oral or parenteraladministration the dosage can vary from about 0.01 mg to about 1000 mgper day of a compound of the invention.

In any event, the medical practitioner, or other skilled person, will beable to determine routinely the actual dosage, which will be mostsuitable for an individual patient. The above-mentioned dosages areexemplary of the average case; there can, of course, be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

Wherever the word “about” is employed herein, for example in the contextof amounts (e.g. values, weights, volumes, moles), temperatures, degreesof crystallinity, degrees of degradation, degrees of purity, degrees ofdissolution and doses of active ingredients, it will be appreciated thatsuch variables are approximate and as such may vary by ±10%, for example±5%, ±2%, or ±1% from the numbers specified herein.

Compounds of the invention have the advantage that they are in a formwhich provides for improved ease of handling, and may be produced informs which have improved chemical and solid state stability whencompared to forms prepared previously. Thus, compounds may be stablewhen stored over prolonged periods. In particular, the D-form (seeExample 2 hereinafter) may have improved thermodynamic stability,compared to forms of Compound I previously prepared.

Compounds of the invention also have improved solubility andhygroscopicity profiles when compared to previously-available forms.

Compounds of the invention may also have the advantage that they may beprepared in good yields, in a higher purity, in less time, moreconveniently, and at a lower cost, than forms prepared previously.

Compounds of the invention may also have the advantage that they may bemore efficacious than, be less toxic than, be longer acting than, bemore potent than, produce fewer side effects than, be more easilyabsorbed than, and/or have a better pharmacokinetic profile (e.g. higheroral bioavailability and/or lower clearance) than, and/or have otheruseful pharmacological, physical, or chemical properties over, knowncompounds (e.g. previously known forms of Compound I), whether for usein the above-stated indications or otherwise.

The invention is illustrated, but in no way limited, by the followingexamples, with reference to the enclosed figures in which:

FIG. 1 shows an X-ray powder diffractogram for the crystalline form ofCompound I anhydrate, using X-rays of wavelength 1.5418 Å, obtained byway of Example 1 (cps (intensity) values are plotted against ° 2-Thetavalues).

FIG. 2 shows an X-ray powder diffractogram for the crystalline form ofCompound I anhydrate, using X-rays of wavelength 1.5418 Å, obtained byway of Example 2 (cps (intensity) values are plotted against ° 2-Thetavalues).

FIG. 3 shows DSC for the crystalline form of Compound I anhydrateobtained by way of Example 2.

GENERAL PROCEDURE X-Ray Powder Diffraction Method Description

It is known that an X-ray powder diffraction pattern may be obtainedwhich has one or more measurement errors depending on measurementconditions (such as equipment or machine used). In particular, it isgenerally known that intensities in an X-ray powder diffraction patternmay fluctuate depending on measurement conditions. Therefore it shouldbe understood that the Forms A and D of the present invention are notlimited to the crystals that provide X-ray powder diffraction patternsidentical to the X-ray powder diffraction pattern shown in FIGS. 1 and2, and any crystals providing X-ray powder diffraction patternssubstantially the same as those shown in FIGS. 1 and 2 fall within thescope of the present invention. A person skilled in the art of X-raypowder diffraction is able to judge the substantial identity of X-raypowder diffraction patterns.

Persons skilled in the art of X-ray powder diffraction will realise thatthe relative intensity of peaks can be affected by, for example, grainsabove 30 microns in size and non-unitary aspect ratios, which may affectanalysis of samples. The skilled person will also realise that theposition of reflections can be affected by the precise height at whichthe sample sits in the diffractometer and the zero calibration of thediffractometer. The surface planarity of the sample may also have asmall effect. Hence the diffraction pattern data presented are not to betaken as absolute values.

Generally, a measurement error of a diffraction angle in an X-ray powderdiffractogram is about 5% or less, in particular plus or minus 0.5°2-theta. Typically plus or minus 0.2° 2-theta. Such degree of ameasurement error should be taken into account when considering theX-ray powder diffraction patterns in FIGS. 1 and 2 and when readingTables 1, 2 and 2A. Furthermore, it should be understood thatintensities might fluctuate depending on experimental conditions andsample preparation (preferred orientation).

X-ray powder diffraction (XRPD) analysis was performed on samplesprepared according to standard methods, for example those described inGiacovazzo, C. et al (1995), Fundamentals of Crystallography, OxfordUniversity Press; Jenkins, R. and Snyder, R. L. (1996), Introduction toX-Ray Powder Diffractometry, John Wiley & Sons, New York; Bunn, C. W.(1948), Chemical Crystallography, Clarendon Press, London; or Klug, H.P. & Alexander, L. E. (1974), X-ray Diffraction Procedures, John Wileyand Sons, New York.

X-ray diffraction analyses were performed using a Thermo ARL X'TRA(wavelength of X-rays 1.5418 Å, Cu source, Voltage 45 kV, filamentemission 44 mA) for 152 minutes from 2 to 40°. Calculation of peakpositions (° 2-theta) was done and they may vary in the range ±0.5°2-theta. However, the data presented in Table 2A on Form D was obtainedusing a Bruker D4 machine and a wavelength of 1.5418 Å.

It will be appreciated by a skilled person in the art that XRPDintensities may vary when measured for essentially the same crystallineform, for example, preferred orientation.

Differential Scanning Calorimetry

Analytical Instrument: TA Instruments Q1000 DSC. Typically less than 5mg of material contained in a 40 μl aluminium pan fitted with a lid washeated over the temperature range 25° C. to 300° C. at a constantheating rate of 10° C. per minute. A purge gas using nitrogen wasused—flow rate 100 ml per minute.

Reference Example 1 (R)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)ethanol

i) 5,6-O-Isopropylidene-L-ascorbic acid

To a mixture of L-ascorbic acid (65 kg, 369 mol), acetone (283 kg) and2,2-dimethoxypropane (46 kg, 443 mol) was charged p-toluenesulfonic acid(1.1 kg, 5.5 mol). Temperature was adjusted to 25±5° C. The slurry wasstirred for 2 hours, during which time nitrogen was frequently flushedthrough the bottom valve to prevent material from settling at the bottomof the reactor. NMR analysis (solvent: D₂O) then showed 98.5%conversion.

Heptanes (222 kg) were charged and the temperature adjusted to 5±5° C.The reaction mixture was stirred for at least 30 minutes beforefiltering. Remains of the acetonide product in the reactor were rinsedonto the filter cake using the mother liquors. The filter cake waswashed with heptanes (111 kg) and dried at 50° C. to give5,6-O-isopropylidene-L-ascorbic acid (73 kg, 336 mol) as an almost whitepowder. Yield: 91%.

¹H NMR (400 MHz, d₆-DMSO, with maleic acid and TFA) δ 4.71 (d, J=3.0 Hz,1H), 4.28 (m, 1H), 4.11 (dd, J=7.0, 8.4 Hz, 1H), 3.90 (dd, J=6.3, 8.4Hz, 1H), 1.27 (s, 6H).

ii) (R)-Methyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyacetate

5,6-O-Isopropylidene-L-ascorbic acid (58.8 kg, 272 mol) was charged tosodium hydroxide solution (27.5 kg, 50%, 340 mol) diluted with water(294 kg). and the temperature was adjusted to 30±5° C. Sodiumbicarbonate (57 kg, 680 mol) was charged and the mixture was agitatedfor 15 minutes before the temperature was increased to 40±5° C. Hydrogenperoxide 35% (55 kg, 562 mol) was added to the mixture at 35-60° C. overa period of more than 60 minutes. The reaction mixture was agitated fortwo hours before NMR analysis (solvent: D₂O) showed <1% residualstarting material.

Sodium sulfite (4.2 kg, 33 mol) was charged to the reactor and afterstirring for 30 minutes, a test for peroxides was negative.

After charging more sodium bicarbonate (34 kg, 408 mol), the mixture washeated to 70±5° C. and agitated for at least one hour before NMRanalysis (solvent: D₂O) showed 98.5% conversion to the nextintermediate,(2R)-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl](hydroxy)ethanoic acid.

Approximately 150 L of water was stripped off under reduced pressurebefore filtering off salts. The filter cake was washed with water (30L).

NMP (330 kg) was charged to the combined mother liquors/wash and thetemperature was adjusted to 30±5° C. Methyl iodide (83 kg, 585 mol) wascharged and the reactor closed. The temperature was adjusted to 55±5° C.and the reaction mixture was left to react for at least 120 minutesbefore NMR analysis (solvent: D₂O) showed 6% of the residual hydroxyethanoic acid intermediate.

Sodium sulfite (56 kg, 446 mol) dissolved in water (147 kg) was chargedand the mixture was agitated for 30 minutes. The solution was extractedfour times for 10 minutes at 30±10° C. using 406 kg toluene in eachextraction. The combined organic phase was concentrated by stripping offsolvent, under reduced pressure and a maximum temperature to of 70° C.,until a residual volume of approximately 350 L was reached. The solutionwas cooled to below 30° C. and transferred to steel barrels over aMillipore filter to give (R)-methyl2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyacetate solution intoluene (359 kg, 9.4%, 177 mol). Yield: 65%.

¹H NMR consistent with commercially available sample of the sub-titleproduct.

iii) (R)-Methyl2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(tosyloxy)acetate

From (R)-Methyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyacetatesolution in toluene (359 kg, 9.4%, 177 mol), toluene was distilled offunder reduced pressure and a maximum temperature of 70° C. untilcondensation ceased.

Acetonitrile (153 kg) was charged and the temperature was adjusted to25±5° C. Triethylamine (41 kg, 405 mol), 4-(dimethyl amino)pyridine(1.12 kg, 9.2 mol) and then, over about 30 minutes, a solution ofp-toluenesulfonyl chloride (52.5 kg, 276 mol) in acetonitrile (146 kg)were added at 25±5° C. After stirring the reaction mixture for anadditional three hours, NMR analysis (solvent: d₆-DMSO) showedacceptable conversion (94%).

MTBE (235 kg) and water (326 kg) were charged and the two-phase systemwas agitated for about 3 hours, after which time HPLC analysis showedthe level of p-toluenesulfonyl chloride to be <0.1% of total peak area.The temperature was adjusted to 25±5° C. and then allowed to separatefor 15 minutes. The aqueous phase was taken and extracted with furtherMTBE (156 kg) before discarding. The 2 organic phases were pooledtogether and washed with water (326 kg). Then the organic phase waswashed 4 times with sodium chloride (16 kg each portion) solution inwater (140 kg each portion), each for 5-10 minutes at 25±5° C. Then theorganic phase was washed twice with water (185 kg per portion) each for5-10 minutes at 25±5° C. NMR analysis (solvent: d₆-DMSO) then showed <2%NMP (residual from the starting solution), by moles relative to thesulfonate ester intermediate.

Activated carbon (6.0 kg) was charged and the slurry was agitated for 15minutes at 25±5° C. before the carbon was filtered off in two parallelbag filter. A cartridge filter of 0.6 μm was used after the bag filters.The filters and pipes were rinsed with MTBE (27 kg).

The mother liquors and rinse were combined and reduced in volume bystripping off solvent, under reduced pressure and a maximum temperatureof 50° C., until condensation ceased. Heptanes (106 kg) was charged andthe solution was reduced once again by stripping off solvent, underreduced pressure and a maximum temperature of 50° C., until condensationceased, leaving about 60 L solution in the reactor. MTBE (185 kg) wascharged followed, after adjusting the temperature to 25±5° C., byheptanes (75 kg). The solution was cooled to 0-5° C. over no less than30 minutes and heptanes (150 kg) was added over an additional 20minutes. The slurry was agitated for one hour at 0-5° C. and thenfiltered. The filter cake was washed with a mixture of MTBE (16 kg) andheptanes (30 kg). The wet product was charged to a vacuum tray dryer anddried at 35° C. (at less than 100 mbar), to give (R)-methyl2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(tosyloxy)acetate (51.3 kg, 154mol) as a light brown powder. Yield: 87%.

¹H NMR (400 MHz, CDCL₃) δ 7.83 (m, 2H), 7.35 (m, 2H), 4.84 (d, J=4.8 Hz,1H), 4.46 (m, 1H), 4.04 (dd, J=6.6, 9.1 Hz, 1H), 3.97 (dd, J=5.2, 9.1Hz, 1H), 3.70 (s, 3H), 2.45 (s, 3H), 1.30 (s, 3H), 1.29 (s, 3H).

iv) (S)-2,2-Dimethyl-4-((R)-oxiran-2-yl)-1,3-dioxolane

(R)-Methyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(tosyloxy)acetate(76.1 kg, 221 mol) was dissolved in methanol (57 kg) and dichloromethane(208 kg).

Methanol (14 kg), dichloromethane (53 kg) and one-third of the startingmaterial solution (74 mol) were charged to the reactor. The solution wastempered to 10-15° C. Then, sodium borohydride (6.3 kg, 169 mol) wascharged in 18 portions to the reactor holding the temperature 8-15° C.The mixture was stirred for half an hour after complete addition. Thenext one-third of the starting material solution (74 mol), and moresodium borohydride (6.3 kg, 169 mol) were charged, followed by ahalf-hour stir, using the same procedure as before. This procedure wasagain repeated with the final one-third of the starting materialsolution (74 mol) and more sodium borohydride (6.3 kg, 169 mol). HPLCanalysis then showed >99.9% conversion to the intermediate(S)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyethyl4-methylbenzenesulfonate.

Dichloromethane (200 kg) was charged to the reaction mixture. Sodiummethoxide solution in methanol (43 kg, 30%, 239 mol) was dosed at 20-25°C. for 60 minutes. After approximately half an hour, HPLC analysisshowed 99.7% consumption of the intermediate alcohol.

A solution of sodium acetate (25 kg) in water (230 L) was charged to thereaction mixture. The mixture was stirred for 10-15 minutes at 20-25° C.After separation for 15 minutes the lower organic phase was removed. Theupper aqueous phase was extracted with dichloromethane (376 kg). Thelower organic phase was removed, combining with the first organic phase,and the aqueous phase was discarded.

Water (359 L) was charged to the combined organic phases. After stirringfor 10-15 minutes at 20-25° C. and settling for 15 minutes, the lowerorganic phase was transferred to a reactor containing sodium sulphate(63 kg).

The volume of the mixture was reduced to 310 L by stripping off solvent,and then the sodium sulphate was filtered off. The filter cake waswashed with dichloromethane (94 kg). The combined liquors werethoroughly mixed and then discharged to steel drums via a polypropylenebag filter to give (S)-2,2-dimethyl-4-((R)-oxiran-2-yl)-1,3-dioxolanesolution in DCM (467.5 kg, 6.2%, 203 mol) as a clear yellow liquid.Yield: 91%.

A sample, free from solvents, may be isolated on a small scale byevaporation of solvent and then distilling under vacuum.

¹H NMR (isolated sample, 400 MHz, d₆-DMSO) δ 4.01 (dd, J=6.6, 8.2 Hz,1H), 3.92 (m, 1H), 3.72 (dd, J=5.8, 8.2 Hz, 1H), 3.03 (ddd, J=2.6, 4.1,5.2 Hz, 1H), 2.77 (dd, J=4.1, 5.0 Hz, 1H), 2.58 (dd, J=2.6, 5.0 Hz, 1H),1.34 (s, 3H), 1.27 (s, 3H).

v) (R)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)ethanol

From (S)-2,2-Dimethyl-4-((R)-oxiran-2-yl)-1,3-dioxolane solution indichloromethane (465 kg, 6.2%, 200 mol), dichloromethane was distilledat 41-42° C. and replaced by THF (129 kg). Distillation was continued at60° C. until a set volume in the reactor was reached (235 L). Lithiumaluminium hydride (LAH) solution in THF (26.4 kg, 10%, 70 mol) was dosedto the reactor at 22° C. and after subsequent stirring at 25° C. forapproximately one hour, GC analysis showed >99.9% consumption of thestarting material.

Small portions of water were added via a charging funnel at a rate whichwas adjusted to control temperature and foaming. A total of 2.6 litresof water (1 L per kg LAH) was added. Sodium hydroxide solution (2.6 kg,15%, 1 L per kg LAH) was added in the same manner as described forwater. Water (7.9 L, 3 L per kg LAH) was charged once more via thecharging funnel using the same procedure as before.

The slurry was filtered and the filter cake was washed with THF (36 kg).The filtrate was concentrated by stripping off THF, at a maximumtemperature of 85° C., until condensation ceased. 2-MeTHF (129 kg) wascharged to the reactor, and then solvent was distilled off to reach asolution volume of approximately 120 L. KF analysis showed <0.1% water.The solution was discharged via a cartridge filter to a PE-lined drum togive (R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethanol solution (103 kg,27%, 187 mol) as a clear, light yellow liquid. Yield: 94%.

A sample, free from solvents, may be isolated on a small scale byevaporation of solvent and then distilling under vacuum.

¹H NMR (isolated sample, 400 MHz, d₆-DMSO) δ ppm 4.77 (d, J=5.1 Hz, 1H),3.95 (dd, J=8.0, 6.2 Hz, 1H), 3.76 (dd, 8.0, 6.0 Hz, 1H), 3.70 (m, 1H),3.46 (m, 1H), 1.29 (s, 3H), 1.25 (s, 3H), 1.07 (d, J=6.2 Hz, 3H).

Example 1 Form A Compound I Anhydrate

Compound I, i.e.N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-{[(1R,2S)-2,3-dihydroxy-1-methylpropyl]oxy}-4-pyrimidinyl]-1-azetidinesulfonamide(for instance, as prepared in accordance with Example 47 in WO2006/024823) is used in the following procedure.1. Charge Compound I MAPI (43.94 g, 100% mass=40.0 g) and acetonitrile(160 mL, 4.0 rel vols) to vessel 1 and stir at 20° C.2. Screen the mixture into vessel 2 and rinse vessel 1 and the lineswith acetonitrile (20 mL, 0.50 rel vols). Stir, and heat to 55° C.

-   -   Whatman grade 3 filter papers (6 μm pore size, 32 mm diameter        circular filter area) were used.    -   The filter paper may be swapped for a fresh one (if filtration        using suction slows down).    -   After the filtration, the solution was weighed and found to be a        smaller than expected mass. It was topped up with a small charge        of acetonitrile (10 mL, 0.25 rel vols), to correct for the        evident losses to evaporation.        3. Charge phosphoric acid (8.80 g, 0.22 rel wt) followed by        water (20 mL, 0.50 rel vols) to the stirring vessel 2 solution        and change the set point to 51° C.    -   The acid and water may be charged together if this is more        convenient.        4. Sample the reaction to determine conversion after 10 and 35        minutes.    -   It is important to dilute the samples for the HPLC analysis as        soon as possible after taking them, noting the time at which the        dilutions were actually made.    -   Conversion was 45, 81 and 93% after 10.5, 32 and 57 mins,        respectively. Moved on to step 5 at t=135 mins.

5. Heat to 71° C.

-   -   Step 6 should be started as soon as possible after reaching        around 68° C.        6. Charge water (204 mL, 5.1 rel vols), slowly enough to        maintain the temperature above 67° C.

7. Cool to 65° C.

-   -   It is important that the reaction temperature be as close as        possible to the set point before proceeding. 2-3° C. below may        result in very rapid crystallisation and associated problems.        3° C. higher may go above the clear point and from there        crystallisation cannot be started.        8. If necessary, generate a seed for crystallisation by diluting        a sample of the solution (0.48 mL, 0.012 rel vols) with water        (1.44 mL, 0.036 rel vols). Mix well and then charge the slurry        back into the solution.        9. Hold at 65° C. for 40 mins.        10. Cool by 6° C. at a rate of 3° C./hr (65-59° C. over 2.0        hours), then by 8° C. at 4° C./hr (59-51° C.) and finally to        20° C. at 6° C./hr (51-20° C. over 5.2 hrs).        11. Check that the crystallisation has reached a suitable        equilibrium.        12. Filter, wash the cake twice with 3:2 water:acetonitrile v:v        (2×120 mL, 2×3.00 rel vols), incorporating a rinse of vessel 2        for each wash, and then dry at 60° C. to constant mass.        Alternatively, Form A may be prepared as follows:        1. Charge        N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy]-4-pyrimidinyl]-1-azetidinesulfonamide        (for instance, as prepared in accordance with Example 47 in WO        2006/024823) (43.94 g, 100% mass=40.0 g) and acetonitrile (160        mL, 4.0 rel vols) to vessel 1 and stir at 20° C.        2. Screen the mixture into vessel 2 and rinse vessel 1 and the        lines with acetonitrile (20 mL, 0.50 rel vols). Stir, and heat        to 55° C.    -   Whatman grade 3 filter papers (6 μm pore size, 32 mm diameter        circular filter area) were used.    -   The filter paper may be swapped for a fresh one (if filtration        using suction slows down).    -   After the filtration, the solution was weighed and found to be a        smaller than expected mass. It was topped up with a small charge        of acetonitrile (10 mL, 0.25 rel vols), to correct for the        evident losses to evaporation.    -   3. Charge phosphoric acid (8.80 g, 0.22 rel wt) followed by        water (20 mL, 0.50 rel vols) to the stirring vessel 2 solution        and change the set point to 51° C.        -   The acid and water may be charged together if this is more            convenient.            4. Sample the reaction to determine conversion after 10 and            35 minutes.    -   It is important to dilute the samples for the HPLC analysis as        soon as possible after taking them, noting the time at which the        dilutions were actually made.    -   Conversion was 45, 81 and 93% after 10.5, 32 and 57 mins,        respectively. Moved on to step 5 at t=135 mins

5. Heat to 71° C.

-   -   Step 6 should be started as soon as possible after reaching        around 68° C.        6. Charge water (204 mL, 5.1 rel vols), slowly enough to        maintain the temperature above 67° C.

7. Cool to 65° C.

-   -   It is important that the reaction temperature be as close as        possible to the set point before proceeding. 2-3° C. below may        result in very rapid crystallisation and associated problems.        3° C. higher may go above the clear point and from there        crystallisation cannot be started.        8. Hold at 65° C. for 40 mins.        9. Cool by 6° C. at a rate of 3° C./hr (65-59° C. over 2.0        hours), then by 8° C. at 4° C./hr (59-51° C.) and finally to        20° C. at 6° C./hr (51-20° C. over 5.2 hrs).        10. Check that the crystallisation has reached a suitable        equilibrium.        11. Filter, wash the cake twice with 3:2 water:acetonitrile v:v        (2×120 mL, 2×3.00 rel vols), incorporating a rinse of vessel 2        for each wash, and then dry at 60° C. to constant mass to give        Compound I as Form A.

Alternatively, form A may be prepared by dissolvingN-[2-[[(2,3-difluorophenyl)methyl]thio]-6-{[(1R,2S)-2,3-dihydroxy-1-methylpropyl]oxy}-4-pyrimidinyl]-1-azetidinesulfonamide(as prepared fromN-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy]-4-pyrimidinyl]-1-azetidinesulfonamidein accordance with Example 47 in WO 2006/024823) in water (6.2 relativevolumes) and acetonitrile (5 relative volumes) by heating to 70° C. Oncethis temperature is reached and the solution is clear, the solution isslowly cooled to 20° C. Crystallisation normally commences at atemperature close to 60° C. to give Form A.

The XRPD pattern of Form A using a wavelength of 1.5418 Å on a ThermoARL X'TRA XRD machine is shown in FIG. 1 and is tabulated in Table 1below.

TABLE 1 Relative Intensity (%) approx. 25-100% = “vs”, Angle approx.10-25% = “s”, approx. 3-10% = (2-Theta °) “m” and approx. 1-3% = “w” 4.4vs 8.7 vs 9.7 s 9.9 vs 11.4 vs 13.1 vs 14.8 s 15.5 s 15.9 m 16.3 s 17.6vs 17.8 vs 18.2 s 18.5 s 19.0 m 19.2 vs 19.5 vs 19.9 vs 20.1 m 21.9 m22.4 vs 23.8 s 24.1 vs 24.4 s 24.9 m 26.1 s 26.5 sThis anhydrate form of Compound I was highly crystalline.

Example 2 Form D Compound I Anhydrate

Form A of Compound I as obtained for instance by the process describedin Example 1 above was converted to Form D.

Form A of Compound I was slurried in methanol at 50° C. for 6 weeks toobtain the D-form.

It may also be possible to obtain the D form by slurrying the product ofExample 47 in WO 2006/024823 in methanol at 50° C. for 6 weeks.

Using DSC, form D had a melting point of 152.7° C. (onset). See FIG. 3below.

The XRPD pattern of the form D using a wavelength of 1.5418 Å on aThermo ARL X'TRA XRD machine is shown in FIG. 2 and is tabulated inTable 2 below.

TABLE 2 Relative Intensity (%) approx. 25-100% = “vs”, Angle approx.10-25% = “s”, approx. 3-10% = (2-Theta °) “m” and approx. 1-3% = “w” 4.4vs 8.7 vs 9.7 vs 11.5 s 12.9 vs 13.1 vs 14.5 s 18.0 vs 19.0 vs 19.1 vs19.3 s 19.5 s 19.9 vs 21.0 s 21.9 s 22.5 vs 23.9 s 24.5 s 25.1 s 25.3 s27.0 s 28.6 m 28.8 s 29.1 s 30.4 s 34.6 m 36.4 mThe XRPD pattern of the form obtained by way of Example 1 using awavelength of 1,5418 Å on a Bruker D4 XRD machine is tabulated in Table2A below.

TABLE 2A D value 2-Theta ° % d = 20.009 4.4 85.3 d = 10.068 8.8 100.0 d= 9.029 9.8 73.9 d = 8.428 10.5 12.4 d = 7.630 11.6 23.4 d = 6.822 13.058.5 d = 6.725 13.2 68.4 d = 6.088 14.5 11.8 d = 5.647 15.7 12.9 d =5.493 16.1 11.4 d = 5.048 17.6 14.7 d = 4.899 18.1 94.3 d = 4.731 18.717.0 d = 4.647 19.1 27.9 d = 4.614 19.2 27.7 d = 4.577 19.4 26.5 d =4.527 19.6 31.0 d = 4.434 20.0 55.3 d = 4.356 20.4 19.2 d = 4.305 20.614.8 d = 4.219 21.0 14.9 d = 4.155 21.4 13.1 d = 4.049 21.9 24.4 d =4.039 22.0 26.5 d = 3.942 22.5 51.0 d = 3.781 23.5 16.3 d = 3.706 24.038.4 d = 3.618 24.6 23.4 d = 3.529 25.2 33.0 d = 3.506 25.4 38.2 d =3.421 26.0 8.5 d = 3.368 26.4 16.4 d = 3.297 27.0 14.1 d = 3.109 28.79.7 d = 3.090 28.9 16.2 d = 3.064 29.1 18.4 d = 2.962 30.1 12.9 d =2.933 30.4 24.8 d = 2.889 30.9 11.6 d = 2.770 32.3 9.1 d = 2.728 32.88.4 d = 2.638 34.0 8.5 d = 2.588 34.6 15.2 d = 2.461 36.5 10.9 d = 2.36338.0 6.0 d = 2.329 38.6 11.6This anhydrate form of Compound I was also highly crystalline and wasalso more thermodynamically stable than the A-form obtained by means ofExample 1 (see Example 3 below).

Example 3 Form D Compound I Anhydrate

Modification D can be generated using an anti-solvent crystallizationutilizing ethanol as the solvent and water as the anti-solvent.

An 80% saturated solution of the compound is prepared in ethanol, forexample by dissolving 1 relative weight of the compound in 83 relativevolumes of ethanol at a temperature of 25° C. (equivalent to 12 mg ofAZD 5069 in 1 mL of ethanol). The solution can be prepared fromcrystalline material of form A or from amorphous material. To thissolution 166 relative volumes of water (i.e. twice the volume of waterwith respect to the ethanol) are added, either continuously over aperiod of time or in several aliquots. Upon is addition of water thecompound crystallizes as modification D and can be isolated byfiltration from the slurry.

Example 4 Form D Compound I Anhydrate (Seeding Method)

Form D was also prepared in 80% yield by a seeding method, whichinvolved dissolving Compound I (e.g. one relative ‘weight’) in a solvent(such as an alcohol, e.g. isopropanol; e.g. 30 relative volumes orethanol; 15 relative volumes); stirring at elevated temperature (e.g.70° C.) for instance for a period of time (which may be several hours)to achieve full dissolution; continuing stirring at elevated temperature(e.g. 55° C.; i.e. a temperature lower than that required to achievedissolution) for several hours (e.g. overnight); seeding with Form D ofCompound I (e.g. 0.1 weight %); cooling to a lower temperature (e.g. 20°C.); and filtering.

Example 5 Thermodynamic Stability

Competitive slurry trials were performed between the A-form (obtained byExample 1) and the D-form (obtained by Example 2).

Competitive slurries containing the A-form and D-form in methanol wereheld at any temperatures ranging from about 5° C. to about 50° C. It wasfound that the D-form remained stable under these conditions. However,the A-form transforms to the D-form.

Complete conversion of the A-form to the D-form takes place, if theslurry is held at a particular temperature for a sufficient duration oftime.

This shows that the D-form is a thermodynamically more stable form thanthe A-form, at least in the relevant particular temperature range, andhence the D-form may be even more advantageous than the A-form for useas a medicament.

1. A crystalline form of N-[2-[[(2,3-di:fluorophenyl)methyl]thio]-6-{[(1R,2S)-2,3-dihydroxy-1-methylpropyl]oxy}-4-pyrimidinyl]-1-azetidinesulfon-amide (also referred to as “Compound I”), characterised by a powder X-ray diffraction pattern, measured using a wavelength of X-rays 1.5418 A, comprising at least one crystalline peak with a 2-Theta value (in degrees) of 21.0, 28.8 and/or 29.1.
 2. A compound/form as claimed in claim 1 characterised by a powder X-ray diffraction pattern, measured using a wavelength of X-rays 1.5418 A, comprising at least 2 crystalline peaks with a 2-Theta value (in degrees) of 21.0, 28.8 and/or 29.1.
 3. A compound/form as claimed in claim 2 characterised by a powder X-ray diffraction pattern, measured using a wavelength of X-rays 1.5418 A, comprising at least 3 crystalline peaks with a 2-Theta value (in degrees) of 21.0, 28.8 and/or 29.1.
 4. A compound/form as claimed in claim 1 characterised by a powder X-ray diffraction pattern, measured using a wavelength of X-rays 1.5418 A, comprising a further crystalline peak with a 2-Theta value (in degrees) selected from of 12.9 and 18.0.
 5. A compound/form as claimed in claim 1 characterised by a powder X-ray diffraction pattern, measured using a wavelength of X-rays 1.5418 A, comprising crystalline peaks with a 2-Theta value (in degrees) of 12.9, 13.1, 18.0, 21.0, 22.5, 25.1, 25.3, 28.8, 29.1 and 30.4.
 6. A crystalline form of Compound I, characterised by a powder X-ray diffraction pattern, measured using a wavelength of X-rays 1.5418 A, comprising at least one crystalline peak with a 2-Theta value (in degrees) of around 12.9, 18.0 and/or 21.0.
 7. A crystalline form of Compound, I which has a melting point (onset) of 152.7° C.
 8. A compound/form as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.
 9. A pharmaceutical formulation including a compound/form as claimed in claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
 10. A compound/form as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease/condition in which modulation of chemokine receptor activity is beneficial.
 11. The use of a compound/form as defined in claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease/condition in which modulation of chemokine receptor activity is beneficial.
 12. A method of treatment of a disease/condition in which modulation of chemokine receptor activity is beneficial, which method comprises the administration of a compound/form as defined in claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment.
 13. The method of claim 12, wherein the disorder is asthma, allergic rhinitis, COPD, bronchiectasis, inflammatory bowel disease, irritable bowel syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer.
 14. A combination product comprising: (a) the compound/form as defined in claim 1, or a pharmaceutically acceptable salt thereof; and (b) one or more active ingredient that is useful in the treatment of a disease/condition in which modulation of chemokine receptor activity is beneficial, or a pharmaceutically-acceptable salt thereof.
 15. A combination product comprising: (a) pharmaceutical formulation including the compound/form of claim 1, or a pharmaceutically acceptable salt thereof, (b) an active ingredient that is useful in the treatment of a disease/condition in which modulation of chemokine receptor activity is beneficial, or a pharmaceutically-acceptable salt thereof, and (c) a pharmaceutically-acceptable adjuvant, diluent or carrier.
 16. A combination product comprising: a kit of parts comprising components: (a) a pharmaceutical formulation including a compound/form as defined in claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, and (b) a pharmaceutical formulation including an active ingredient that is useful in the treatment of a disease/condition in which modulation of chemokine receptor activity is beneficial, or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other. 